A novel unbiased method reveals progressive podocyte globotriaosylceramide accumulation and loss with age in females with Fabry disease

Behzad Najafian; Aurelio Silvestroni; Alexey Sokolovskiy; Camilla Tøndel; Einar Svarstad; Bogdan Obrisca; Gener Ismail; Myrl D Holida; Michael Mauer

doi:10.1016/j.kint.2022.03.023

A novel unbiased method reveals progressive podocyte globotriaosylceramide accumulation and loss with age in females with Fabry disease

Kidney Int. 2022 Jul;102(1):173-182. doi: 10.1016/j.kint.2022.03.023. Epub 2022 Apr 26.

Authors

Behzad Najafian¹, Aurelio Silvestroni², Alexey Sokolovskiy², Camilla Tøndel³, Einar Svarstad⁴, Bogdan Obrisca⁵, Gener Ismail⁵, Myrl D Holida⁶, Michael Mauer⁷

Affiliations

¹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA. Electronic address: najafian@uw.edu.
² Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
³ Department of Pediatrics, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁴ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁵ Discipline Nephrology-Fundeni Clinical Institute, Department of Nephrology, Urology, Immunology and Immunology of Transplant, Dermatology, Allergology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
⁶ Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Health Care, Iowa City, Iowa, USA.
⁷ Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.

Abstract

While females can suffer serious complications of Fabry disease, most studies are limited to males to avoid confounding by mosaicism. Here, we developed a novel unbiased method for quantifying globotriaosylceramide (GL3) inclusion volume in affected podocytes (F+) in females with Fabry disease independent of mosaicism leading to important new observations. All podocytes in male patients with Fabry are F+. The probability of observing random profiles from F+ podocytes without GL3 inclusions (estimation error) was modeled from electron microscopic studies of 99 glomeruli from 40 treatment-naïve males and this model was applied to 28 treatment-naïve females. Also, podocyte structural parameters were compared in 16 age-matched treatment-naïve males and females with classic Fabry disease and 11 normal individuals. A 4^th degree polynomial equation best described the relationship between podocyte GL3 volume density and the estimation error (R² =0.94) and was confirmed by k-fold cross-validation. In females, this model showed that age related directly to F+ podocyte GL3 volume (correlation coefficient (r = 0.54) and podocyte volume (r = 0.48) and inversely to podocyte number density (r = -0.56), (all significant). F+ podocyte GL3 volume was significantly inversely related to podocyte number density (r = -0.79) and directly to proteinuria. There was no difference in F+ podocyte GL3 volume or volume fraction between age-matched males and females. Thus, in females with Fabry disease GL3 accumulation in F+ podocytes progresses with age in association with podocyte loss and proteinuria, and F+ podocyte GL3 accumulation in females with Fabry is similar to males, consistent with insignificant cross-correction between affected and non-affected podocytes. Hence, these findings have important pathophysiological and clinical implications.

Keywords: Fabry; GL3; biopsy; globotriaosylceramide; mosaicism; pathology; podocyte.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Fabry Disease* / complications
Female
Humans
Male
Podocytes*
Proteinuria / etiology
Trihexosylceramides

Substances

Trihexosylceramides
globotriaosylceramide

Grants and funding

U54 NS065768/NS/NINDS NIH HHS/United States